Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
  • A23K20/163—Sugars; Polysaccharides
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K20/00—Accessory food factors for animal feeding-stuffs
  • A23K20/10—Organic substances
  • A23K20/195—Antibiotics
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K40/00—Shaping or working-up of animal feeding-stuffs
  • A23K40/20—Shaping or working-up of animal feeding-stuffs by moulding, e.g. making cakes or briquettes
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K40/00—Shaping or working-up of animal feeding-stuffs
  • A23K40/25—Shaping or working-up of animal feeding-stuffs by extrusion
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23K—FODDER
  • A23K50/00—Feeding-stuffs specially adapted for particular animals
  • A23K50/40—Feeding-stuffs specially adapted for particular animals for carnivorous animals, e.g. cats or dogs
  • A23K50/42—Dry feed
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
• • A—HUMAN NECESSITIES
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  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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• • A—HUMAN NECESSITIES
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  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
  • A61K38/13—Cyclosporins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
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  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

• the present invention relates to an easy-to-use, safe, efficacious, and stable veterinary formulation consisting of a highly palatable ductile chewable veterinary composition comprising an effective amount of one or more ingredients that are active against animal pests, pathogens or animal diseases; of meat flavoring; of partially gelatinized starch; of a softener; and of up to 9% of water.
• the present invention also relates to a method of controlling said animal pests or pathogens and of curing or preventing said animal diseases by feeding an animal with said highly palatable ductile chewable veterinary composition. Further, the invention relates to a process for producing said highly palatable ductile chewable veterinary composition by cold extrusion.
• the highly palatable ductile chewable veterinary composition controls animal pests like endo-parasites, such as worms, and simultaneously ecto-parasites, such as biting insects like fleas, on pets.
• the pesticidally effective ingredient is dispensed as the animal chews the product.
• Veterinary products can be administered to warm-blooded animals in very different ways depending on their mode of action and their ability to be taken up either by the treated animal or the target pest.
• veterinary products can be administered, for example, topically as pour-on or spot-on formulations, in form of shampoos, showers, as a dip, bath or spray, in form of a collar, and in many variants of these application forms. They can also be administered systemically, for example, orally, parenterally and in certain cases even transdermally.
• systemic administration forms are: via injection, as a tablet, capsule, bolus, drink, feed additive and the like.
• Each of these administration forms can have advantages-or disadvantages-depending onJhe-actual-situation-andJhe-animal-thaHs-in need of such a treatment.
• Treatment of herd animals, like horses, cattle, sheep or poultry usually requires different administration methods than for the treatment of single animals, such as pets like dogs and cats.
• the present inventors recognized that in the field of animal health the dosage form and especially the palatability of the dosage form, i.e. the natural acceptance of the drug plays the decisive role.
• the underlying problems are outlined hereinafter.
• medicaments may be administered in a wide variety of application forms, such as tablets, coated tablets, emulsions, injection solutions, suppositories and the like, because the discipline and the desire to recover in human patients can be relied upon, in the case of animals practical problems are soon encountered, since a few application forms, such as the usage of suppositories, either have to be dispensed with all together or other forms, such as injections, must only be carried out by the veterinarian.
• Treating humans with medicines is generally not problematic, because the human patient follows the advice of the doctor or reads the directions on the leaflet in the package and complies with them since this is in his own interest, and because the manufacturer usually prepares the tablet, capsule or coated tablet in a form which is appropriate for oral consumption and-has been-tailored for human patients ⁇
• An animal must have a natural willingness to take a medicinal preparation orally, which means that the medical preparation must taste well and be palatable.
• an individual animal or " a few animals can also be forced to take a medicament, by making it swallow or by injecting it.
• forced methods are not only unacceptable to large animal operations but also to single dogs and cats which tend to bite or scrape if they are not willing to be treated. This is why animal treatment can be very labor-intensive or can require the intervention of a veterinarian and this ultimately leads to increase of costs.
• the chewable composition according to the present invention is not only suitable for replacing the treatment with a tablet or capsule. These chewables can also easily be mixed with conventional non-medicated feed pellets if herds of animals have to be treated.
• the chewables according to the present invention are taken up by animals without causing any acceptance problems. Their handling is easy and safe, and can be adapted to the need either of an individual animal like a cat or a dog or to a herd animals like sheep and cows.
• the tablet is not noticed by the dog at all and is simply gulped down, and in other cases it remains uneaten in the dog bowl.
• cats are considerably more fastidious in their eating habits. Only in the rarest cases can a tablet or coated tablet be mixed with the formulated food, without them noticing it immediately and rejecting it.
• cats also to not exactly chew their food, they generally break it down with a few small bites. They thereby damage the protective coating of a tablet or capsule and release the unpleasant tasting active ingredient. Attempts to mix the active ingredient directly with the feed likewise fail, because either the degree of dilution is insufficient to neutralize the unpleasant taste or the active ingredient breaks down too rapidly when in contact with the feed.
• any other active ingredient which is suitable for animals can be administered according to the present invention, but especially those active ingredients that have the taste disadvantages mentioned initially and are therefore not willingly taken orally by animals.
• a diversity of individual active ingredients or mixtures of active ingredients may be considered 7 -e ⁇ grthose-acting-against-external (ecto)-o ⁇ nternal-(endo)-parasites-Oractive — ingredients acting against animal diseases including viral or bacterial infections, behavioral disorders, such as hypo- or hyper-activity, inflammatory diseases, and auto-immune diseases.
• the active ingredient can be a pesticide or a medicament or a mixture of both.
• the present invention deals with an optimized application form for veterinary compositions rather than with the treatment of animals with a specific class of active ingredients.
• the present invention provides an easy-to-use, safe, powerful, and stable veterinary formulation consisting of a highly palatable ductile chewable veterinary composition, which allows to administer orally almost each and any active ingredient to a warm-blooded animal, provided that this active ingredient or mixture of active ingredients is at the administered dose physiologically acceptable to the animal, does not display unacceptable side effects and, what is most important, exhibits after oral uptake systemic activity.
• any active ingredient or class of active ingredients mentioned hereinafter is nothing but a non-limiting example of suitable active ingredients.
• the application form of the present invention is actually not limited to existing active ingredients but also suitable for each and any active ingredient developed in the future provided that the future active ingredient meets the main characteristics explained hereinbefore.
• the highly palatable ductile chewable veterinary composition of the present invention is in principle a medicated food product and everybody working in this area is aware of the technical problems that arise in context with the production of medicated feed.
• stability of the active ingredient is very crucial. It is a matter of fact that many potent active compounds are somewhat unstable (temperature-sensitive), above all when in contact with feed material, especially close contact to vegetable and animal materials, during conventional extrusion of feed pellets, result in considerable losses of active ingredient.
• the dried organic starting material of animal or vegetable origin is ground, is intimately mixed with the active ingredient, that is to say is substantially homogenized, and then is moistened with water or steam and is -compressed-into-pellets-at-elevated ⁇ temperatures-and-under-pressures-of-aroundJ00-kbar.
• said high pressures and the permanent high temperatures in the range of 60- 100°C are disadvantageous and do not only dramatically reduce the viscosity of the pellets but result in a considerable lost of active ingredient.
• Unsuccessful attempts at such stabilization include, for example, (1) reduction of the active ingredient surface area by means of compression into granules, a very great variety of granule sizes having been tried; (2) sealing of the said active ingredient granules in a very great variety of protective layers, for example gelatin or various sugars and coatings; (3) enclosure of the active ingredient within porous materials such as, for example, various celluloses, starches, silicic acids or zeolites, with or without additional protective layers; and (4) chemical modification of the basic macrocyclic structure of the active ingredient. Although in a few cases chemical modification has resulted in improved stability of the compound per serit'has-simultaneously-resulted ⁇ n-loss-ofactivity; — .
• the chewable veterinary composition of the present invention contains a relatively high amount of meat material, this has obviously when combined with the appropriate amount of partially gelatinized starch, no adverse effect on the stability of the active ingredient. It actually turned out that the chewable veterinary composition of the present invention is a very stable product that can be stored at room temperature over many months without significant loss or degradation of active ingredient. Tests with stored material demonstrate that the palatability is not decreased and the efficacy of the active ingredient stays at a high level.
• the present invention provides a safe, easy to use and stable product that is at least as efficacious as conventional oral application forms, like tablets or capsules.
• the chewable veterinary composition of the present invention one can combat all kinds of pa asites ⁇ -Ex-ternafparasites7also-called-eeto-parasites7-are-understood-to-be-parasites- which normally live on the animal, i.e. an the animal's skin or in the fur.
• biting insects such as mosquitoes, blowfly, fleas or lice, or members of the order Acarina, e.g. mites or ticks.
• Suitable products against external parasites include insecticides and acaricides. It does not matter what their mode of action actually is. They can be e.g. chitin synthesis inhibitors, growth regulators; juvenile hormones; adulticides.
• the active ingredient can be broadband insecticides, broad-band acaricides.
• the active ingredient can be a killer or a deterrent or repellent. It can affect e.g. only adult stages or juvenile stages of the parasite or may affect any stage. The only prerequisite is that the active ingredient acts systemically. This means that it is not decomposed after oral uptake but transported by the body fluids to the skin or organ where the parasite uses to live.
• acaricide a systemically acting acaricide from one of the following well-known classes of acaricides including: antibiotic acaricides such as abamectin, doramectin, eprinomectin, ivermectin, milbemectin, nikkomycins, selamectin, tetranactin, and thuringiensin; bridged diphenyl acaricides such as azobenzene, benz ⁇ ximate, benzyl benzoate, bromopropylate, chlorbenside, chlorfenethol, chlorfenson, chlorfensulphide, chlorobenzilate, chloropropylate, dicofol, diphenyl sulfone, dofenapyn, fenson, fentrifanil, fluorbenside, proclonol, tetradifon, and tetrasul;
• antibiotic acaricides such as abam
• Suitable insecticides acting either as adulticides or insect growth regulators can be chosen from a variety of well-known different chemical classes such as chlorinated hydrocarbons, organophosphates, carbamates, pyrethroids, formamidines, borates, phenylpyrazoles, and macrocyclic lactones (previously known as avermectins).
• Prominent representatives of adulticides/insect killers are imidacloprid, fenthion, fipronil, allethrin, resmethrin, fenvalerate, permetrin, maiathion and derivatives thereof. Insect adulticides kill the insect in almost any development stage either by contact or as a stomach poison.
• IGRs insect growth regulators
• benzoylphenylureas such as diflubenzuron, lufenuron, noviflumuron, hexaflumuron, triflumuron, and teflubenzuron or substances like fenoxycarb, pyriproxifen, methoprene, kinoprene, hydroprene, cyromazine, buprofezin, pymetrozine and derivatives thereof.
• Insect growth inhibitors or insect growth regulators are products or materials that interrupt or inhibit the life cycle of a pest.
• the highly palatable ductile chewable veterinary composition according to the present invention is also very suitable for administering active ingredients that combat internal parasites (endo-parasites) such as worms living in the blood or in organs of the animal.
• the active ingredient can be an anthelmintic (dewormer).
• Anthelmintics are a heterogeneous group of drugs but they are selectively toxic to worms.
• the drugs can achieve this by either inhibiting the metabolic process vital to the parasite, or by causing the parasite to be exposed to higher concentration of drug than are the hosts cells, which means that one makes use of the existence of an advantageous therapeutic window.
• Anthelmintics can affect the target parasite during treatment by interfering with the integrity of parasite cells, inhibiting neuromuscular transmission and coordination, or mechanisms which protect against host immunity, that ultimately lead to the starvation, neuromuscular paralysis, death and expulsion of the parasite.
• Anthelmintics are commonly administered by drench, paste, orally, or by injection. The drugs are absorbed into the blood stream and widely diffused.
• Trematodes such as Alaria alata and Opisthorchis tenuicollis
• Cestodes such as Taenia hydatigena, Taenia pisiformis, Taenia ovis, Hydatigena Taenia taeniaeformis, Echinococcus granulosus, Echinococcus multilocularis, Dipylidium caninum, Diphyliohothrium Mum, Multiceps multiceps, Multiceps se alis, Mesocestoides lineatus, and Mesocestoides corti ; and Nematodes such as Ancylostoma caninum, Uncina a stenocephaia, Toxocara canis, Toxocara cati, Toxascaris leonina, Strongyloides stercoralis, Filaroides osieri, Capilla a aerophila, Capillaria plica, Capillari
• Internal parasites within the present invention include all species of worm infestation (helminthes) but also bacteria ' and viruses causing bacterial and viral infections, in particular " those that infest the organs or parts of the body, such as the lungs, heart, alimentary tract or extremities, or which spread through the whole organism.
• the anthelmintic can be selected from endo-parasiticides and endecticides including one of the following well-known groups of dewormers such as macrocyclic lactones (sometimes called simply macrolides), benzimidazoles, pro-benzimidazoles, imidazothiazoles, tetrahydropyrimidines, organophosphates and piperazines.
• dewormers such as macrocyclic lactones (sometimes called simply macrolides), benzimidazoles, pro-benzimidazoles, imidazothiazoles, tetrahydropyrimidines, organophosphates and piperazines.
• a most preferred group of anthelmintics consists of the more modern natural or chemically modified macrocyclic lactones (macrolides), such as avermectins, milbemycins and derivatives thereof, including prominent representatives such as Ivermectin, Doramectin, Moxidectin, Selamectin, Emamectin, Eprinomectin, Milbemectin, Abamectin, Milbemycin oxime, Nemadectin, and a derivative thereof, in free form or in the form of a physiologically acceptable salt.
• macrocyclic lactones such as avermectins, milbemycins and derivatives thereof, including prominent representatives such as Ivermectin, Doramectin, Moxidectin, Selamectin, Emamectin, Eprinomectin, Milbemectin, Abamectin, Milbemycin oxime, Nemadectin, and a derivative thereof
• the macrocyclic lactones are most preferred because they exhibit a broad spectrum of activity. Most of them exhibit ecto and in parallel endo-parsiticidal activity. Therefore, they are-also-ealled-endectoeidesT MaerocyelieHactones-bindJo-glutamated-chlorine-channels causing in the first instance paralysis and later on the death of the parasite.
• Ri is hydrogen or one of radicals
• R 4 is hydroxyl, -NH-CH 3 or -NH-OCH 3 ;
• Ivermectin is 22,23-Dihydroabamectin; 22,23-dihydroavermectin B 1 ; or 22,23-dihydro C- 076B 1 , wherein X is -C(H)(OH)- ; Y is -C(H 2 )-; R- . is the radical
• R 2 is either -CH(CH 3 )-CH 3 or -CH(CH 3 )-C 2 H 5 and the bond between atoms 22 and 23 represents a single bond.
• Ivermectin is known from US-4,199,569.
• R 2 is cyclohexyl and the bond between atoms 22 and 23 represents a double bond.
• Doramectin is known from US-5, 089,480.
• R 2 is cyclohexyl; and the bond between atoms 22 and 23 represents a single bond.
• Selamectin is known e.g. from: ECTOPARASITE ACTIVITY OF SELAMECTIN; A novel endectocide for dogs and cats. A Pfizer Symposium, held in conjunction with The 17th international Conference of the World Association for the Advancement of Veterinary Parasitology, 19 August 1999. Copenhagen, Denmark.
• R 2 is -CH(CH 3 )-CH 3 , or -CH(CH 3 )-C 2 H 5 , and the bond between atoms 22 and 23 represents a double bond.
• Emamectin is known from US-4,874,749.
• R 2 is -CH(CH 3 )-CH 3 , or -CH(CH 3 )-C 2 H 5 , and the bond between atoms 22 and 23 represents a double bond.
• Eprinomectin is known from US-4,427,663.
• X is -C(H)(OH)- ; Y is -C(H 2 )-; Ri is hydrogen; R 2 is -CH 3 , or -C 2 H 5 ; and the bond between atoms 22 and 23 represents a single bond.
• Milbemectin is known from US-3, 950,360.
• R 2 is -CH(CH 3 )-CH 3 , or -CH(CH 3 )-C H 5 ; and the bond between atoms 22 and 23 represents a double bond.
• Abamectin is known from US-4,310,519.
• Milbemycin oxim is milbemycin A 4 5-oxime; milbemycin A 3 5-oxime, wherein X is - C(H)(OH)- ; ; Y is -C(H 2 )-; Ri is hydrogen; R 2 is -CH(CH 3 )-CH 3 , or -CH(CH 3 )-C 2 H 5 , and the bond between atoms 22 and 23 represents a single bond. Milbemycin oxim is known from US-4,547,520.
• R 2 is -CH 3 or C 2 H 5 , and the bond between atoms 22 and 23 represents a single bond. This compound is known from WO 01/83500.
• Nemadectin is known from US-4,869,901.
• Benzimidazoles, benzimidazole carbamate and pro-benzimidazoles interfere with energy metabolism by inhibition of polymerization of microtubules and include very potent compounds such as thiabendazole, mebendazole, fenbendazole, oxfendazole, oxibendazole, albendazole, luxabendazole, netobimin, parbendazole, flubendazole, cyclobendazole, febantel, thiophanate and derivatives thereof.
• Imidazothiazoles are cholinergic agonists and include highly active compounds such as tetramisole, levamisole, and derivatives thereof.
• Tetrahydropyrimidines act are also cholinergic agonists and include highly active compounds such as morantel, pyrantel, and derivatives thereof.
• Organophosphates are inhibitors of cholinesterase. This class includes potent compounds such as dichlorvos, haloxon, trichlorfon, and derivatives thereof.
• Piperazines exhibit anticholinergic action and block neuromuscular transmission. This class includes highly active compounds such as piperazine and derivatives thereof.
• Salicylanilide selected from closantel, tribromsalan, dibromsalan, oxychlozanide, clioxanide, rafoxanide, brotianide, bromoxanide and derivatives thereof.
• the anthelmintic (dewormer) a preferred embodiment consist of a combination of a macrocyclic lactone and an anthelmintic selected from the group consisting of Albendazole, Clorsulon, Cydectin, Diethylcarbamazine, Febantel, Fenbendazole, Haloxon, Levamisole, Mebendazole, Morantel, Oxyclozanide, Oxibendazole, Oxfendazole, Oxfendazole, Oxamniquine, Pyrantel, Piperazine, Praziquantel, Thiabendazole, Tetramisole, Trichlorfon, Thiabendazole, and derivatives thereof. Most preferred is Praziquantel.
• said anthelmintic combination can contain in addition to the dewormers a parasiticidally effective amount of an insecticide, acaricide or an insecticide and an acaricide.
• a parasiticidally effective amount of an insecticide, acaricide or an insecticide and an acaricide can contain in addition to the dewormers a parasiticidally effective amount of an insecticide, acaricide or an insecticide and an acaricide.
• an antibiotic for treating bacterial disease can be included in order to broaden the activity spectrum towards ecto-parasites.
• Suitable antimicrobial active ingredients are, e.g. various penicillins, tetracyclines, sulfonamides, cephalosporins, cephamycins, aminoglucosids, trimethoprim, dimetridazoles, erythromycin, framycetin, fruazolidone, various pleuromutilins such as thiamulin, valnemulin, various macrolides, streptomycin and substances acting against protozoa, e.g. clopidol, salinomycin, monensin, halofuginone, narasin, robenidine, etc.
• Behavioral disorders include e.g. separation worry or travel sickness of dogs and cats.
• a suitable compound acting against behavioral disorders is e.g. clomipramine.
• the chewable combination according to the present invention may also contain an active ingredient for the treatment of disfunctions or hypo-activity.
• Dysfunction or hypo-activity is understood to include functions like autoimmune disorders, which deviate from the norm, whether through inborn or acquired damage to individual organs or tissue.
• This complex also includes rheumatic diseases, pathological changes to joints, bones or internal organs, and much more.
• a prominent representative of compounds that can be used in this complex area is cyclosporine and derivatives thereof.
• the term "animal disease” even includes different types of cancer and metastasis progression in connective tissues that are common in animals. In this field bisphosphonates like coledronate, clodronate, etidronate, pamidronate and alendronate play an important role.
• Said bisphosphonates can also be administered in the treatment or prophylaxis of ulcers, rheumatoid arthritis and other arthitides, and periodontitis.
• Another suitable class of active ingredients encompasses anti-inflammatory agents such as benzenesulfonamides like Deracoxib, which is extremely suitable for the control of pain and inflammation associated with osteoarthritis. Further anti-inflammatory agents are diclofenac and derivatives thereof.
• the administration problems depicted in connection with conventional oral dosage forms can be very easily resolved and chewable products can be prepared, which are taken orally by the animals without causing any problems.
• the present invention overcomes the disadvantages and shortcomings of the prior art by providing an easy-to-use, safe, powerful, and stable veterinary formulation consisting of a highly palatable ductile chewable veterinary composition which is produced by an extrusion process wherein the product is extruded at or near room temperature, and where the extruder is cooled down below room temperature, preferably to 5-10°C.
• the palatable ductile chewable composition constitutes a veterinary composition and is administered orally.
• composition is capable of killing endo-parasites and ecto-parasites and/or can be used for treating prophylactic or curative animal diseases, and it is useful for the treatment of any warm-blooded non-human animal, including herd animals, like horses, cattle, sheep or poultry and preferably pets like dogs and cats.
• the highly palatable ductile chewable veterinary composition of the invention is composed of an organic composition which contains an effective amount of one or more active ingredients, preferably an effective amount of a mono, binary or ternary mixture of organic compounds ⁇ capable of controlling ecto-parasites, endo-parasites or bacterial or viral pathogens or a combination of ecto-parasites, endo-parasites, bacterial or viral pathogens.
• the highly palatable ductile chewable veterinary composition of the invention contains a parasiticidally or anti-pathogenically effective amount of one or more active ingredients.
• parasiticidally effective amount refers to that amount of active ingredient in the composition which will fully control the target parasite which means that 95-100%, preferably 98-100% or close to 100% of the parasites are killed and the active ingredient is nevertheless well tolerated.
• anti-pathogenically effective amount refers to that amount of active ingredient in the composition which will efficiently cure a bacterial, viral or behavioral disease or if administered prophylactically will suppress the outbreak of such a disease.
• the highly palatable ductile chewable veterinary composition of the invention comprises an effective amount of one or more ingredients that are active against animal pests, pathogens or animal diseases; it further comprises meat flavoring and partially gelatinized starch, and it comprises of a softener; and of up to 9 % (w/w), preferably 3-7 % (w/w), most preferred 4-6 % (w/w), of water. It is essential that that during the extrusion process the extruder is cooled down below room temperature. A temperature range of 5-10°C is ideal.
• a highly palatable ductile chewable veterinary composition that comprises (A) an effective amount of one or more ingredients that are active against animal pests, pathogens or animal diseases; (B) meat flavoring; (C) partially gelatinized starch; (D) a softener; and (E) optionally up to 9 % (w/w) water.
• a highly palatable ductile chewable veterinary composition as defined above capable of controlling endo-parasites and simultaneously ecto-parasites of non-human animals.
• a highly palatable ductile chewable veterinary composition as defined above comprising 20 to 30 % (w/w) of a natural meat flavoring.
• a highly palatable ductile chewable veterinary composition as defined above comprising 25 to 70 % (w/w) of partially gelatinized starch.
• a highly palatable ductile chewable veterinary composition as defined above comprising 10 to 20 % (w/w), preferably about 1 1-15 % (w/w), of a softener, based upon the weight of the partially gelatinized starch.
• a highly palatable ductile chewable veterinary composition as defined above comprising up
• a highly palatable ductile chewable veterinary composition as defined above comprising 1 to 10 % (w/w), preferably 3 to 7 % (w/w) of a sweetener.
• a highly palatable ductile chewable veterinary composition as defined above comprising 0 to 3.5 % (w/w), preferably 0.01 to 0.5 % (w/w) of an antioxidant.
• a highly palatable ductile chewable veterinary composition as defined above comprising 0 to 5 % (w/w), preferably 0.05 to 2 % (w/w) of a coloring agent.
• a highly palatable ductile chewable veterinary composition as defined above comprising 0 to 4% (w/w) of sodium chloride.
• a highly palatable ductile chewable veterinary composition as defined above comprising an parasiticidally effective amount of an ecto-parasiticide, an endo-parasiticide, an endectocide or of a combination of a parasiticide selected from the group consisting of an ecto- parasiticide, an endo-parasiticide and an endectocide.
• a highly palatable ductile chewable veterinary composition as defined above comprising an parasiticidally effective amount of an endo-parasiticide or endecticide selected from the group consisting of macrocyclic lactones, benzimidazoles, pro-benzimidazoles , imidazothiazoles, tetrahydropyrimidines, organophosphates and piperazines.
• a highly palatable ductile chewable veterinary composition as defined above comprising an -effective-amount-of-a-natural or-GhemiGally-modified-maGroGyoliG lactone-of-for-mula-H-)- -
• Ri is hydrogen or one of radicals
• R 4 is hydroxyl, -NH-CH 3 or -NH-OCH 3 ;
• a highly palatable ductile chewable veterinary composition as defined above comprising an effective amount of a natural or chemically modified macrocyclic lactone of formula ( I ) wherein X is -C(H)(OH)- ; Y is -C(H 2 )-; R-i is the radical
• R 2 is -CH 3 or C 2 H 5 , and the bond between atoms 22 and 23 represents a single bond.
• a highly palatable ductile chewable veterinary composition as defined above comprising an effective amount of a macrocyclic lactone in combination with an effective amount of an anthelmintic selected from the group consisting of Albendazole, Clorsulon, Cydectin, Diethylcarbamazine, Febantel, Fenbendazole, Haloxon, Levamisole, Mebendazole, Morantel, Oxyclozanide, Oxibendazole, Oxfendazole, Oxfendazole, Oxamniquine, Pyrantel, Piperazine, Praziquantel, Thiabendazole, Tetramisole, Trichlorfon, Thiabendazole, and a derivative thereof.
• an anthelmintic selected from the group consisting of Albendazole, Clorsulon, Cydectin, Diethylcarbamazine, Febantel, Fenbendazole, Haloxon, Levamisole, Mebendazole, Morantel, Oxyclozan
• a highly palatable ductile chewable veterinary composition as defined above comprising additionally an effective amount of an insecticide, acaricide or an insecticide and an • -aoarieider — — * ⁇ — - *
• a highly palatable ductile chewable veterinary composition as defined above comprising an effective amount of milbemycin oxime and praziquantel.
• a highly palatable ductile chewable veterinary composition as defined above comprising an effective amount of iufenuron, praziquantel and milbemycin oxime.
• a highly palatable ductile chewable veterinary composition as defined above comprising an effective amount of cyclosporin.
• a highly palatable ductile chewable veterinary composition as defined above comprising an effective amount of an antimicrobial selected from the group consisting of a penicillin, tetracycline, sulfonamide, cephalosporin, cephamycin, aminoglucosid, trimethoprirn, dimetridazole, erythromycin, framycetin, fruazolidone, pleuromutilin, streptomycin and a compound that is active against protozoa.
• an antimicrobial selected from the group consisting of a penicillin, tetracycline, sulfonamide, cephalosporin, cephamycin, aminoglucosid, trimethoprirn, dimetridazole, erythromycin, framycetin, fruazolidone, pleuromutilin, streptomycin and a compound that is active against protozoa.
• a highly palatable ductile chewable veterinary composition as defined above comprising an effective amount of compound that is active against behavioral including separation worry or travel sickness of dogs and cats.
• Another preferred embodiment of the present invention is a method of controlling said animal pests or pathogens and of curing or preventing said animal diseases by feeding an animal with said highly palatable ductile chewable veterinary composition.
• Yet another preferred embodiment of the present invention is a method of controlling said animal-pests-or-pathogens-and- ⁇ f- ⁇ Uring- ⁇ r-preventing-said-animal-diseases--by feeding-an animal with said highly palatable ductile chewable veterinary composition.
• Yet another preferred embodiment of the present invention is a process for the production of a highly palatable ductile chewable veterinary composition as defined above, comprising (i) feeding the hopper of an extruder with an effective amount of one or more ingredients that are active against animal pests, pathogens or animal diseases; meat flavoring; partially gelatinized starch; a softener; and up to 9% (w/w) of water, (ii) cooling constantly down the mixture of active ingredients and carriers so that the temperature of the extrudate in the extruder does during the whole extrusion process at no time exceed 40°C, (iii) pressing the extrudate through a die that is decisive for the shape of the chewable product, and (iv) cutting the extrudate that leaves the extruder into equal pieces.
• Yet another preferred embodiment of the present invention is a process as defined above wherein the hopper of the extruder is fed continuously and simultaneously with pre-mixture (1) and pre-mixture (2), wherein pre-mixture (1) consist of a homogenized mixture of one or more active ingredients and partially gelatinized starch, and pre-mixture (2) consists of a homogenized mixture of meat flavoring, a softener and optionally of a carrier selected from the group consisting of a sweetener, softener, an antioxidant, a coloring agent and sodium chloride.
• Yet another preferred embodiment of the present invention is a process as defined above wherein the extruder is cooled down below room temperature.
• a further preferred embodiment of the present invention is a method of controlling nonhuman animal pests or nonhuman animal pathogens or of curing or preventing nonhuman animals diseases comprising feeding an animal with a palatable ductile chewable veterinary composition as defined above.
• a further preferred embodiment of the present invention is a method as defined above, wherein the palatable ductile chewable veterinary composition consist of one chewable portion containing an effective amount of a compound or mixture of compounds capable of controlling nonhuman animal pests or nonhuman animal pathogens or of curing or preventing nonhuman animals diseases.
• a further preferred embodiment of the present invention is a method as defined above, wherein the amount of active ingredient is adjusted to the bodyweight of the nonhuman animal that is in need of the treatment.
• Another preferred embodiment of the present invention is the use of (A) an effective amount of one or more ingredients that are active against animal pests, pathogens or animal diseases; (B) meat flavoring; (C) partially gelatinized starch; (D) a softener; (E) up to 9% water; and an active ingredient suitable for combating animal pests, pathogens or animal diseases for the preparation of a highly palatable ductile chewable veterinary composition.
• Another preferred embodiment of the present invention is the use as defined above, comprising 20 to 30 % (w/w) of a natural meat flavoring.
• Another preferred embodiment of the present invention is the use as defined above, wherein the natural meat flavoring comprises 20 to 55 % (w/w) fat.
• Another preferred embodiment of the present invention is the use as defined above, comprising 25 to 70 % (w/w) of partially gelatinized starch.
• Another preferred embodiment of the present invention is the use as defined above, wherein the partially gelatinized starch comprises 12 to 17 % (w/w) of gelatinized starch.
• Another preferred embodiment of the present invention is the use as defined above, comprising 10 to 20 % (w/w) of a softener, based upon the weight of the partially gelatinized starch.
• Another preferred embodiment of the present invention is the use as defined above, wherein the softener is selected from the group consisting of glycerol, polyethylene glycol and polypropylene glycol.
• Another preferred embodiment of the present invention is the use as defined above, comprising 3 to 7 % (w/w) of water.
• Another preferred embodiment of the present invention is the use as defined above, wherein the animal pests are external animal parasites or internal animal parasites or both.
• Another preferred embodiment of the present invention is the use as defined above, comprising 1 to 10 % (w/w) of a sweetener.
• Another preferred embodiment of the present invention is the use as defined above, comprising 0 to 3.5 % (w/w) of an antioxidant.
• Another preferred embodiment of the present invention is the use as defined above, comprising 0 to 5 % (w/w) of a coloring agent.
• Another preferred embodiment of the present invention is the use as defined above, comprising 0 to 4% (w/w) of sodium chloride.
• Another preferred embodiment of the present invention is the use as defined above, comprising an parasiticidally effective amount of an ecto-parasiticide, an endo-parasiticide, an endectocide or of a combination of a parasiticide selected from the group consisting of an ecto-parasiticide, an endo-parasiticide and an endectocide.
• Another preferred embodiment of the present invention is the use as defined above, wherein the ecto-parasiticide is active against insects, members of the order Acarina or insects and members of the order Acarina.
• Another preferred embodiment of the present invention is the use as defined above, wherein the ecto-parasiticide is an insecticide which is either an insect adulticides or insect growth regulators.
• Another preferred embodiment of the present invention is the use as defined above, comprising an parasiticidally effective amount of an endo-parasiticide or endecticide selected from the group consisting of macrocyclic lactones, benzimidazoles, pro-benzimidazoles , imidazothiazoles, tetrahydropyrimidines, organophosphates and piperazines.
• an endo-parasiticide or endecticide selected from the group consisting of macrocyclic lactones, benzimidazoles, pro-benzimidazoles , imidazothiazoles, tetrahydropyrimidines, organophosphates and piperazines.
• R 4 is hydroxyl, -NH-CH 3 or -NH-OCH 3 ;
• macrocyclic lactone is a compound of the formula ( I ) wherein X is -C(H)(OH)- ; Y is - C(H 2 )-; R-i is the radical
• R 2 is -CH 3 or C 2 H 5 , and the bond between atoms 22 and 23 represents a single bond.
• endecticide is a macrocyclic lactone is selected from the group consisting of avermectins, milbemycins and derivatives thereof, in free form or in the form of a physiologically acceptable salt.
• macrocyclic lactone is selected from the group consisting of Ivermectin, Doramectin, Moxidectin, Selamectin, Emamectin, Eprinomectin, Milbemectin, Abamectin, Milbemycin oxime, Nemadectin, and a derivative thereof, in free form or in the form of a physiologically acceptable salt.
• Another preferred embodiment of the present invention is the use as defined above, comprising an effective amount of a macrocyclic lactone in combination with an effective amount of an anthelmintic selected from the group consisting of Albendazole, Clorsulon, Cydectin, Diethylcarbamazine, Febantel, Fenbendazole, Haloxon, Levamisole, Mebendazole, Morantel, Oxyclozanide, Oxibendazole, Oxfendazole, Oxfendazole, Oxamniquine, Pyrantel, Piperazine, Praziquantel, Thiabendazole, Tetramisole, Trichlorfon, Thiabendazole, and a derivative thereof.
• an anthelmintic selected from the group consisting of Albendazole, Clorsulon, Cydectin, Diethylcarbamazine, Febantel, Fenbendazole, Haloxon, Levamisole, Mebendazole, Morantel, Oxyclozanide,
• Another preferred embodiment of the present invention is the use as defined above, comprising in addition to an endo-parasiticide or an endecticide an effective amount of an insecticide, acaricide or an insecticide and an acaricide.
• Another preferred embodiment of the present invention is the use as defined above, comprising an effective amount of milbemycin oxime and praziquantel.
• Another preferred embodiment of the present invention is the use as defined above, comprising an effective amount of lufenuron, praziquantel and milbemycin oxime.
• Another preferred embodiment of the present invention is the use as defined above, comprising an effective amount of cyclosporin.
• Another preferred embodiment of the present invention is the use as defined above, comprising an effective amount of an antimicrobial selected from the group consisting of a penicillin, tetracycline, sulfonamide, cephalosporin, cephamycin, aminoglucosid, trimethoprim, dimetridazole, erythromycin, framycetin, fruazolidone, pleuromutilin, streptomycin and a compound that is active against protozoa.
• Another preferred embodiment of the present invention is the use as defined above, comprising an effective amount of compound that is active against behavioral including separation worry or travel sickness of dogs and cats.
• An additional preferred embodiment of the present invention is the use of a highly palatable ductile chewable veterinary composition as defined above in a process of controlling nonhuman animal pests or nonhuman animal pathogens or of curing or preventing nonhuman animals diseases.
• the meat flavoring is either a natural product consisting of dried powdered meat derived, for example, from domestic animals and productive livestock, e.g. pigs, horses, cattle, sheep, goats and poultry including chicken, duck, goose and turkey.
• a "meat flavoring” shall refer to natural dried and powdered meat as well as to artificial meat flavorings, which are well-known from the food industry. It has however be recognized that artificial meat flavorings are only suitable for the present invention if they already contain 20-55% (w/w) fat or if this amount of fat is added to the artificial flavoring. Fat that can be added to artificial meat flavorings can be chosen either from animal fats or preferably from plant fats including vegetable oils.
• Unsaturated oils are usually liquid at room temperature and result in products that do not show the desired ductility/softness. They are usually too soft.
• Preferred is the use of saturated/hardened oils/fats that are generally solid at room temperature and lead to chewable compositions showing the desired ductility.
• Fats and oils contain many different fatty acids which affect the body in varying ways. Most simply, they are classified as saturated or unsaturated. Saturated fats sometimes are also called hardened fats, It is the saturated fat found in many animal products. Saturated fats are generally solid at room temperature. They are mainly of animal origin but can also be isolated from plants. Typical examples stemming from plants are cocoa butter and coconut and palm oils.
• Natural and artificial meat flavoring is commercially obtainable from various producers. Natural meat flavoring is, for example, obtainable from: IDF (International Dehydrated Food) INTERNATIONAL DEHYDRATED FOODS, INC. P.O.
• Haarman und Reimer Within the present invention the expression "soft” is used to characterize a product that is not as hard and crunchy as, for example, a cornflake and on the other hand is not as ductile as, for example, a marshmallow.
• the desired ductility/hardness lies somewhere in between. If measured with a commercially available TEXTURE ANALYSER that is commercially available from Stable Micro Systems(TA-XT2 iHR/25), the texture (softness/hardness) of the chewables lies ideally between 6 - 12 N.
• Periodontal disease This disease involves the inflammation and degeneration of tissues that surround and support the teeth, These include the gingiva, alveolar bone, periodontal ligament, and cementum. Periodontitis or the loss of supporting bone is the latest stage of this progressive disorder and is the major cause of tooth loss in old dogs and cats. Animals suffering from periodontitis avoid eating hard and crunchy products because they cause them pain.
• the second important feature of the present invention is the use or partially gelatinized starch.
• This starch contains 10-20% (w/w), preferably about 13-17% (w/w), most preferably 13-17% (w/w) pre-gelatinized starch. This is important as non-gelatinized and completely pre-gelatinized starch do not result in the desired ductility of the final product.
• Starches exhibit thermal stability to about 121 °C.
• Starches are carbohydrates of a general formula (C 6 H 10 O 5 )n and are derived from corn, wheat, oats, rice, potatoes, yucca and similar plants and vegetables. They consist of about 27% linear polymer (amylose) and about 73% branched polymer (amylopectin). The two polymers are intertwined within starch granules. Granules are insoluble in cold water, but soaking in hot water or under steam pressure -r pt ⁇ res ir ⁇ G ⁇ er-i g ⁇ n he oly ⁇ ere ⁇ a pregelatinized starch and has been used in muds for many years.
• pregelatinized starch is water-soluble starch that has undergone irreversible changes by heating in water or steam.
• Many suitable pregelatinized starches are commercially available.
• Naster® Instant which is a pregelatinized Pea Starch with a high gel strength. Due to its high amylose level, it has some remarkable properties. It shows an excellent stability to high temperatures, shearing and to variations in pH and is ideal for use in cold processes.
• a further important component is the softener, which keeps the moisture within the composition and allows to store the final product for weeks and months. It does not become hard and does not dry out.
• the mentioned meat flavoring, partially gelatinized starch and the basic component containing the active ingredient does not contain moisture one should add water during the extrusion process. This has an impact on the flexibility on the chewable veterinary composition of the present invention. It turned out that it is advantageous to adjust the moisture content of the product so that the final product contains water at a concentration equal to or lower than 9 % (w/w), preferably about 3 to 7 % (w/w), more preferably 4 to 6 % (w/w).
• the highly palatable ductile chewable veterinary composition of the present invention is the outcome of a special extrusion process.
• extrusion is a very common thermoforming process widely used in the food industry for the production of customary feed pellets.
• a highly palatable ductile product one has to modify the process and secure that the extrudate is not heated during the whole extrusion process because this leads to hard and crunchy products, to losses of active ingredient, and especially to a decrease of the palatability. Actually, production in the desired manner can easily be achieved.
• the highly palatable ductile chewable veterinary composition of the present invention is conveniently carried out in an injection molding machine or extruder.
• a mixture comprising an effective amount of one or more ingredients that are active against animal pests, pathogens or animal •diseasesr-meaWlav ⁇ ringT-partially-gelatinize is fed through the hopper onto a rotating, reciprocating screw.
• the material moves along the screw towards the tip.
• its temperature is cooled down constantly by means of external coolers around the outside of the barrel and by the shearing action of the screw.
• the cooling process is controlled so that the temperature of the extrudate during the whole extrusion process does not exceed peak temperature of 40°C.
• the extrudate should not reach temperatures higher than said 40°C. It has been found that ideally the product is extruded at or near room temperature, and the extruder is cooled down below room temperature, preferably to 5-10°C. It is then conveyed through the metering zone, where homogenization occurs, to the end of the screw. The homogenized material at the tip is then pressed through a form-determining die to obtain shaped articles of the desired size. The simplest way is cutting the extrudate that leaves the extruder into equal pieces of the desired size. 'Desired' means that each piece contains the appropriate amount of active ingredient. Thus, for example, for big dogs one would produce bigger pieces than for young cats. The amount of active ingredient has to be adapted to the bodyweight of the animal that has to be treated.
• The-highly-palatable-ductile-Ghewable-veterinary-G ⁇ mp ⁇ sitH ⁇ n- ⁇ f4he-present-invention- may- also contain a sweetener for further improving the palatability.
• a sweetener for further improving the palatability.
• Any natural sugar can be used including confectioners sugar, maltitol, xylitol, sorbitol, mannitol, lactose, dextrose, saccharose, glucose or fructose, or any mixture thereof.
• artificial sweeteners known in the art, including saccharin, aspartame and Acesulfame-K may also be used.
• the sweetener is preferably present in an amount of from 1 to 10 % (w/w), preferably between from about 3 to about 7 % (w/w) based on the sweetening power of sucrose.
• the sweetener serves as a palatability enhancer due to its organoleptic properties. Enhancement of the palatability can be especially achieved in those cases where the active ingredient is extremely bitter or exhibits a taste that is absolutely not accepted by the animal.
• the veterinary composition of the present invention may also contain an antioxidant even so it turned out that in most of the cases this is not necessary.
• the antioxidant serves as a preservative which increases the stability of ingredients that are not stable if exposed for a longer period of time to oxygen.
• antioxidant represents the three groups of antioxidants, true anti ⁇ xidants, such as Tenox 2, Tenox PG, Tenox s-1 , ' BHA " (2-t-butyl-4-methoxyphenol), and BHT (2,6-di-t-butyl-4-methylphenol), sodium metabisulfite reducing agents and antoxidant synergists, such as tocopherols (alpha, beta, or delta- tocopherol, tocopherol esters, alpha-tocopherol acetate), alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, edetic acid and its salts, lecithin and tartaric acid.
• true anti ⁇ xidants such as Tenox 2, Tenox PG, Tenox s-1 , ' BHA " (2-t-butyl-4-methoxyphenol), and BHT (2,6-di-t-butyl-4-methylphenol
• antioxidants are resveratrol, quercetin, benzoic acid, Trolox (N- acetylcysteine, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), dimethyl thiourea (DMTU), hesperetin, tetrahydrocurcumin, tetrahydrodemethoxycurcumin, and monothioglycerol.
• Said antioxidant being added in concentrations ranging from 0 to 3.5 % (w/w), preferably 0.01 to 0.5 % (w/w).
• Preferred antioxidant are Tenox 2 and BHA (2-t-butyl- 4-methoxyphenol).
• Sodium chloride may also be added, up to about 4% (w/w), to further improve the palatability of the product and to bind moisture.
• sodium chloride serves like a palatability enhancer.
• the highly palatable ductile chewable veterinary composition of the present invention further may contain a softener.
• the softener for use in the invention serves as a humectant which enhanees4he-flex-ibilit-y-of4he-pet ⁇ ehew-and-retains-moi&ture-so4hat4he4exture- ⁇ f-the-pet-- chew is maintained at ambient temperatures.
• the softener is present in the highly palatable ductile chewable veterinary composition of the present invention at concentrations from about 10-20 % (w/w) and preferably about 11-15% (w/w) based upon the weight of the partially gelatinized starch.
• Suitable softeners include alcohols such as sorbitol, mannitol, hexanol, pentanol and polyols (such as glycerine, propylene glycol, polyethylene glycol, and polypropylene glycol).
• the highly palatable ductile chewable veterinary composition of the present invention may further contain a coloring agent that lead to a better-looking product.
• the coloring agent can be selected from the group of azo dyes, organic or inorganic pigments, or coloring agents of natural origin, preferably from oxides of iron of titanium. Said coloring agent being added in concentrations ranging from 0 to 5 % (w/w), preferably 0.05 to 2 % (w/w).
• a preferred coloring agent is ferric oxide, that is normally used in an amount around 0J % (w/w).
• the extruder used for the production of the chewables according to the present invention is a co-rotating twin screw extruder type BCTG-62/28D with a screw diameter of 62 mm and a screw length of L/D ratio of 28D with a pelleting device from B ⁇ hler AG; Industriestrasse; CH-9240 Uzwil; Switzerland.
• the feeder (delivering the dry blend into the extruder) is obtainable from K-Tron, Switzerland. It is a loss in weight feeder: type K2-ML-T 35 twin screw feeder equipped with a AC (twin auger) screw.
• two pumps are use to deliver glycerin and water separately.
• two chillers are used to maintain an extruder temperature below 10°C.
• the texture (softness/hardness) of the chewy is measured by using a TEXTURE ANALYSER type: TA-XT2 iHR/25 that is commercially available from Stable Micro Systems Ltd. (Headquater: Stable Micro Systems Ltd., Vienna Court, Lammas Road; UK). One measures the peak force (in N) necessary to push a sphere with a velocity of 1 mm/sec to penetrate 2mm into the chewable. The sphere has a diameter of 8 mm.
• the texture of the chewables ⁇ is-measured4o-determine-when4he che ables-are-hard-enOugh4o-be-packaged ' into bins, before they are packaged into blisters. Texture after 24 hours: Typical values lay between 8 and 20 N. Examples
• the 2-Way-formulation containing Milbemycin oxime and Praziquantel is produced as follows:
• the 3-Way-formulation containing Milbemycin oxime, Praziquantel and Lufenuron is produced along the same lines as described for the 2-Way-formulation in Example 1.
• Natural chicken flavor 150.00 g 30.0%
• Example 4 Palatability (acceptance) test for different flavored chewables of a 3-wav formulation with 100 dogs and 100 cats
• 100 male and female dogs of different breeds and age are tested.
• the dogs are divided in 4 groups of 25 dogs of the same bodyweight.
• the testing person offers once a day to each dog one test-chewable which is adapted to the bodyweight of the dog.
• the chewable is offered by hand for 60 seconds. If the dog does not take the formulation it is offered the dog in his empty bowl. The dog has again 60 seconds to take the formulation, if not, it is paced in his/her mouth. If the dog/cat spits it out it is reported as not accepted.
• not more than 5 to 6 different formulations are tested on consecutive days. Each formulation is packaged separately and labeled so that they can be clearly identified. An analogous test is carried out with 100 cats.
• Samples of the highly palatable ductile chewable veterinary composition of the presnet invention are tested for stability under stressing conditions in order to simulate different temperatures and humidity conditions.
• the samples are tested at 25°C/60 rh, 30°C 60% rh and 40°C 75%rh. They are kept in incubators and are analyzed after 3, 6, 9 and 12 months with regard to active ingredient content.
• the analyze of the content of active ingredient of all samples tested at 25°C/60 rh and 30°C 60% rh for 12 months show no difference " in " comparison with identical samples kept in the refrigerator at - 25°C for the same period of time.
• Chewables kept 12 months at 40°C/75%rh show also good stability results which indicate that they would lead to a shelf live for at least 12 months if stored under normal conditions, i.e. 25°C or 30°C and 40-70% rh. No significant difference is seen with regard to the stability of 2-way-formulations containing Milbemycin oxime and Praziquantel and 3-way- formulation containing Milbemycin oxime, Praziquantel and Lufenuron.

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